The present invention relates to novel heterocyclic compounds which contain a heterocylic ring bearing at least one substituent, linked together by a linker containing an acetylenic group, a vinylic group or an azo group. In addition, the present invention relates to pharmaceutical compositions containing novel invention compounds.
Unsaturated heterocylic compounds find a wide variety of uses. For example, compounds of this class find uses as modulators of physiological processes that are mediated by ligand-activated receptors Receptors that are activated by ligands are located throughout the nervous, cardiac, renal, digestive and bronchial systems, among others. Therefore, in the nervous system, for example, heterocyclic compounds are capable of functioning as agonists or antagonists of receptors for neurotransmitters, neurohormones and neuromodulators. Ligand-activated receptors have been identified in a wide variety of species, including humans, other mammals and vertebrates as well as in invertebrate species. Therefore, compounds of this class are also able to modulate receptor-mediated processes throughout phylogeny and find uses in a wide variety of applications, e.g., as insecticides and fungicides.
Accordingly, there is a continuing need in the art for new members of this compound class.
In accordance with the present invention, there is provided a novel class of heterocyclic compounds. Compounds of the invention contain a substituted, unsaturated five, six or seven membered heterocyclic ring that includes at least one nitrogen atom and at least one carbon atom. The ring additionally includes three, four or five atoms independently selected from carbon, nitrogen, sulfur and oxygen atoms. The heterocyclic ring has at least one substituent located at a ring position adjacent to a ring nitrogen atom. This mandatory substituent of the ring includes a moiety (B), linked to the heterocyclic ring via a carbon-carbon double bond, a carbon-carbon triple bond or an azo group. The mandatory substituent is positioned adjacent to the ring nitrogen atom.
Invention compounds are useful for a wide variety of applications. For example heterocyclic compounds can act to modulate physiological processes by functioning as agonists and antagonists of receptors in the nervous system. Invention compounds may also act as insecticides, and as fungicides. Pharmaceutical compositions containing invention compounds also have wide utility.
In accordance with the present invention, there are provided compounds having the structure:
Axe2x80x94Lxe2x80x94B
or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, wherein:
A is a 5-, 6- or 7-membered ring having the structure: 
xe2x80x83wherein at least one of W, X, Y and Z is (CR)p, wherein p is 0, 1 or 2;
the remainder of W, X, Y and Z are each independently O, N or S; and
each R is independently halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted aryl, heterocycle, mercapto, nitro, carboxyl, carbamate, carboxamide, hydroxy, ester, cyano, amine, amide, amidine, amido, sulfonyl or sulfonamide, wherein q is 0, 1, 2 or 3;
L is substituted or unsubstituted alkenylene, alkynylene, or azo; and
B is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cyclohydrocarbyl, substituted or unsubstituted heterocycle, optionally containing one or more double bonds, or substituted or unsubstituted aryl;
provided, that the following compounds are excluded:
the compounds wherein
A is a 6-membered ring wherein:
W, X, Y and Z are (CR)p wherein p is 1; and
R at the W position is hydrogen, lower alkyl, hydroxy, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, unsubstituted or hydroxy-substituted lower alkyleneamino-lower alkyl, lower alkoxy, lower alkanoyloxy, amino-lower alkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy, phthalimido-lower alkoxy, unsubstituted or hydroxy- or 2-oxo-imidazolidin-1-yl-substitued lower alkyleneamino-lower alkoxy, carboxy, esterified or amidated carboxy, carboxy-lower alkoxy or esterified carboxy-lower-alkoxy; R at the X position is hydrogen; R at the Y position is hydrogen, lower alkyl, carboxy, esterified carboxy, amidated carboxy, hydroxy-lower alkyl, hydroxy, lower alkoxy or lower alkanoyloxy; and R at the Z position is hydrogen, lower alkyl, hydroxy-lower alkyl, carboxy, esterified carboxy, amidated carboxy, unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted N-lower alkyl-N-phenylcarbamoyl, lower alkoxy, halo-lower alkyl or halo-lower alkoxy;
L is substituted or unsubstituted alkenylene, alkynylene or azo,
B is substituted or unsubstituted aryl or heterocycle having two or more double bonds, wherein substituents are independently lower alkyl, lower alkenyl, lower alkynyl, phenyl, phenyl-lower alkynyl, hydroxy, hydroxy-lower alkyl, lower alkoxy, lower alkenyloxy, lower alkylenedioxy, lower alkanoyloxy, phenoxy, phenyl-lower alkoxy, acyl, carboxy, esterified carboxy, amidated carboxy, cyano, nitro, amino, acylamino, N-acyl-N-lower alkylamino, halo and halo-lower alkyl, wherein phenyl, phenyl-lower alkynyl, phenoxy, and phenyl-lower alkoxy may bear further substituents; and
the compounds wherein
A is a 6-membered ring wherein:
W, X, Y and Z are (CR)p wherein p is 1; R at the X position is not hydrogen; and R at the W, Y and Z positions are hydrogen;
L is alkenylene or alkynylene; and
B is a substituted or unsubstituted aryl or heterocycle containing two or more double bonds; and
the compounds wherein
A is a 5-membered ring wherein:
one of W, X, Y and Z is (CR)p, and p is 0, two of W, X, Y and Z are (CR)p and p is 1, and the remaining variable ring member is O or S; or
one of W, X, Y and Z is N, one of W, X, Y and Z is (CR)p and p is 1, one of W, X, Y and Z is (CR)p and p is 0, and the remaining variable ring member is O, S or (CR)p, and p is 1; or
two of W, X, Y and Z are N, one of W, X, Y and Z is (CR)p, and p is 0, and the remaining variable ring member is, O or S or (CR)p, and p is 1;
each R is independently hydrogen, nitro, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, C1-C4-haloalkylthio, C3-C6-alkenyl or C3-C8-cycloalkyl;
L is alkynylene; and
B is substituted or unsubstituted aryl, wherein substituents are independently nitro, cyano, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, C1-C4-haloalkylthio, C1-C4-alkoxycarbonyl, C3-C6-alkenyl, phenyl or phenoxy, wherein phenyl and phenoxy may bear further substituents; and
the compounds wherein
A is a 6-membered ring wherein:
W, X, Y and Z are (CR)p, wherein p is 1 and R is hydrogen,
L is alkynylene; and
B is unsubstituted 1-cyclopenten-1-yl or unsubstituted 1-cyclohexen-1-yl; and
the compounds wherein
A is a 5-membered ring wherein:
W is (CR)p, and p is 0, Y and Z are (CR)p, and p is 1, X is N or S; and R is phenyl; or
W is (CR)p, and p is 0, X and Z are (CR)p, and p is 1, Y is O, N or S; and R is phenyl;
L is unsubstituted alkenylene and
B is unsubstituted phenyl; and
the compounds wherein A is a 5-membered ring containing two double bonds, wherein one of W, X, Y and Z is (CR)p, and p is 0, and the remaining ring members are (CR)p and p is 1; and
the compounds wherein A is unsubstituted heterocycle containing two or more double bonds; L is alkenylene or alkynylene, and B is unsubstituted phenyl.
In one aspect, this invention is directed to a compound having the structure:
Axe2x80x94Lxe2x80x94B
or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, wherein B is substituted or unsubstituted pyridyl, thiazolyl, furyl, dihydropyranyl, dihydrothiopyranyl, or piperidinyl; wherein said substitution is by hydroxy, alkoxy, mercapto, aryl, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amido, carboxamido, carbamido, esteryl, sulfonamido, or heterocyclyl other than tetrazolyl, triazolyl, dioxothiazolidinylidenyl, and oxothioxothiazolidinylidenyl.
In an embodiment of this one aspect, this invention is directed to a compound having the structure:
Axe2x80x94Lxe2x80x94B
or enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, wherein
A is 1,3-thiazol-2-yl, optionally substituted with halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted aryl, heterocyclyl, mercapto, nitro, carboxyl, carbamido, hydroxy, esteryl, cyano, amino, amido, or sulfonamide;
L is substituted or unsubstituted alkynylene; and
B is substituted or unsubstituted pyridyl, thiazolyl, furyl, dihydropyranyl, dihydrothiopyranyl, or piperidinyl;
wherein said substitution is by hydroxy, alkoxy, mercapto, aryl, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amido, carboxamido, carbamido, esteryl, sulfonamido, or heterocyclyl other than tetrazolyl, triazolyl, dioxothiazolidinylidenyl, and oxothioxothiazolidinylidenyl.
As employed herein, xe2x80x9chydrocarbylxe2x80x9d refers to straight or branched chain univalent and bivalent radicals derived from saturated or unsaturated moieties containing only carbon and hydrogen atoms, and having in the range of about 1 up to 12 carbon atoms. Exemplary hydrocarbyl moieties include alkyl moieties, alkenyl moieties, dialkenyl moieties, trialkenyl moieties, alkynyl moieties, alkadiynal moieties, alkatriynal moieties, alkenyne moieties, alkadienyne moieties, alkenediyne moieties, and the like. The term xe2x80x9csubstituted hydrocarbylxe2x80x9d refers to hydrocarbyl moieties further bearing substituents as set forth below;
xe2x80x9calkylxe2x80x9d refers to straight or branched chain alkyl radicals having in the range of about 1 up to 12 carbon atoms; xe2x80x9csubstituted alkylxe2x80x9d refers to alkyl radicals further bearing one or more substituents such as hydroxy, alkoxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amido, amide, amidine, amido, carboxyl, carboxamide, carbamate, ester, sulfonyl, sulfonamide, and the like;
xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 6 carbon atoms presently preferred), and xe2x80x9csubstituted alkenylxe2x80x9d refers to alkenyl radicals further bearing one or more substituents as set forth above;
xe2x80x9calkenylenexe2x80x9d refers to straight or branched chain divalent alkenyl moieties having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms (with divalent alkenyl moieties having in the range of about 2 up to 6 carbon atoms presently preferred), and xe2x80x9csubstituted lower alkenylenexe2x80x9d refers to divalent alkenyl radicals further bearing one or more substituents as set forth above;
xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 6 carbon atoms presently being preferred), and xe2x80x9csubstituted alkynylxe2x80x9d refers to alkenyl radicals further bearing one or more substituents as set forth above;
xe2x80x9calkynylenexe2x80x9d refers to straight or branched chain divalent alkynyl moieties having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with divalent alkynyl moieties having two carbon atoms presently being preferred), and xe2x80x9csubstituted alkynylenexe2x80x9d refers to divalent alkynyl radicals further bearing one or more substituents as set forth above;
xe2x80x9ccyclohydrocarbylxe2x80x9d refers to cyclic (i.e., ring-containing) univalent radicals derived from saturated or unsaturated moieties containing only carbon and hydrogen atoms, and having in the range of about 3 up to 20 carbon atoms. Exemplary cyclohydrocarbyl moieties include cycloalkyl moieties, cycloalkenyl moieties, cycloalkadienyl moieties, cycloalkatrienyl moieties, cycloalkynyl moieties, cycloalkadiynyl moieties; spiro hydrocarbon moieties wherein two rings are joined by a single atom which is the only common member of the two rings (e.g., spiro[3.4]octanyl, and the like), bicyclic hydrocarbon moieties wherein two rings are joined and have two atoms in common (e.g., bicyclo[3.2.1]octane, bicyclo [2.2.1]hept-2-ene, and the like), and the like. The term xe2x80x9csubstituted cyclohydrocarbylxe2x80x9d refers to cyclohydrocarbyl moieties further bearing one or more substituents as set forth above;
xe2x80x9ccycloalkylxe2x80x9d refers to ring-containing radicals containing in the range of about 3 up to 20 carbon atoms, and xe2x80x9csubstituted cycloalkylxe2x80x9d refers to cycloalkyl radicals further bearing one or more substituents as set forth above;
xe2x80x9ccycloalkenylxe2x80x9d refers to ring-containing alkenyl radicals having at least one carbon-carbon double bond in the ring, and having in the range of about 3 up to 20 carbon atoms, and xe2x80x9csubstituted cycloalkenylxe2x80x9d refers to cyclic alcenyl radicals further bearing one or more substituents as set forth above;
xe2x80x9ccycloalkynylxe2x80x9d refers to ring-containing alkynyl radicals having at least one carbon-carbon triple bond in the ring, and having in the range of about 3 up to 20 carbon atoms, and xe2x80x9csubstituted cycloalkynylxe2x80x9d refers to cyclic alkynyl radicals further bearing one or more substituents as set forth above;
xe2x80x9carylxe2x80x9d refers to mononuclear and polynuclear aromatic radicals having in the range of 6 up to 14 carbon atoms, and xe2x80x9csubstituted arylxe2x80x9d refers to aryl radicals further bearing one or more substituents as set forth above, for example, alkylaryl moieties;
xe2x80x9cheterocyclexe2x80x9d refers to ring-containing radicals having one or more heteroatoms (e.g., N, O, S) as part of the ring structure, and having in the range of 3 up to 20 atoms in the ring. Heterocyclic moieties may be saturated or unsaturated when optionally containing one or more double bonds, and may contain more than one ring. Heterocyclic moieties include, for example, monocyclic moieties such as imidazolyl moieties, pyrimidinyl moieties, isothiazolyl moieties, isoxazolyl moieties, and the like, and bicyclic heterocyclic moieties such as azabicycloalkanyl moieties, oxabicycloalkyl moieties, and the like. The term xe2x80x9csubstituted heterocyclexe2x80x9d refers to heterocycles further bearin one or more substituents as set forth above;
xe2x80x9cazoxe2x80x9d refers to the bivalent moiety xe2x80x94Nxe2x95x90Nxe2x80x94, wherein each bond is attached to a different carbon atom;
xe2x80x9chalogenxe2x80x9d refers to fluoride, chloride, bromide or iodide radicals.
In accordance with the present invention, A is a 5-, 6- or 7-membered unsaturated heterocyclic moiety, containing a ring having at least one nitrogen atom located on the ring in a position adjacent to a carbon atom which bears a linking moiety as a substituent. The ring further contains 3, 4 or 5 independently variable atoms selected from carbon, nitrogen, sulfur and oxygen. Thus, A can be pyridinyl, imidazolyl, pyridazinyl, pyrimidinyl, pyrazoyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, tetrazinyl, isoxazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, oxadiazinyl, isothiazolyl, thiazoyl, dioxazolyl, oxathiazolyl, oxathiazinyl, azepinyl, diazepinyl, and the like. Those of skill in the art will recognize that multiple isomers exist for a single chemical formula; each of the possible isomeric forms of the various empirical formulae set forth herein are contemplated by the invention. When a variable ring atom is carbon, it bears a hydrogen, or is optionally substituted with halogen, substituted or unsubstituted hydrocarbyl, substituted or unsubstituted aryl, thiol, nitro, carboxyl, ester, cyano, amine, amide, carboxamide, amidine, amido, sulfonamide, and the like, with presently preferred embodiments having no substituent (i.e., q is 0) or bearing the following substituents: halogen, alkyl, containing one up to four carbon atoms, fluorinated alkyl containing one up to four carbon atoms, and amine. Substitution at position Z of the ring is presently preferred.
In accordance with one embodiment of the invention, A is a 5-, 6- or 7-membered ring containing, as ring members, a nitrogen atom and a sulfur atom. Moieties contemplated for use by this embodiment of the invention include those wherein A is isothiazol-3-yl (1,2-thiazol-3-yl), thiazol-4-yl (1,3,-thiazolyl), thiazol-2-yl (1,3-thiazol-2-yl), 1,2-thiazin-3-yl, 1,3-thiazin-4-yl, 1,4-thiazin-3-yl 1,3-thiazin-2-yl, thiazepinyl, and the like. Presently preferred moieties include those wherein A is isothiazol-3-yl (1,2-thiazol-3-yl), thiazol-4-yl (1,3-thiazol-4-yl) and thiazol-2-yl (1,3-thiazol-2-yl).
In accordance with another embodiment of the invention, A is a 5-, 6- or 7-membered ring containing, as ring members, a nitrogen atom and an oxygen atom. Moieties contemplated by this embodiment of the invention include those wherein A is 1,2-oxazin-3-yl, 1,3-oxazin-4-yl, 1,4-oxazin-3-yl, 1,3-oxazin-2-yl, oxazol-2-yl, isoxazol-3-yl, oxazol-4-yl, oxazepinyl, and the like. Presently preferred moieties include those wherein A is oxazol-2-yl, isoxazol-3-yl and oxazol-4-yl.
In accordance with another embodiment of the invention, A is a 5-, 6-, or 7-membered ring containing as ring members two nitrogen atoms. Moieties contemplated by this embodiment of the invention include those wherein A is 3-pyridazinyl (1,2-diazin-3-yl), pyrimidin-4-yl (1,3-diazin-4-yl), pyrazin-3-yl (1,4-diazin-3-yl), pyrimidin-2-yl (1,3-diazin-2-yl), pyrazol-3-yl (1,2-diazol-3-yl), imidazol-4-yl (1,3-isodiazol-4-yl, imidazol-2-yl (1,3-isodiazol-2-yl), diazepinyl, and the like. Presently preferred moieties include those wherein A is 3-pyridazinyl (1,2-diazin-3-yl), pyrimidin-4-yl (1,3-diazin-4-yl), pyrazin-3-yl (1,4-diazin-3-yl), pyrimidin-2-yl (1,3-diazin-2-yl), 1,3-isodiazol-4-yl and 1,3-isodiazol-2-yl.
In accordance with still another embodiment of the invention, A is a 5-, 6-, or 7-membered ring containing, as ring members, three nitrogen atoms. Moieties contemplated by this embodiment of the invention include those wherein A is 1,2,3-triazin-4-yl, 1,2,4-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,3,5-triazin-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, triazepinyl, and the like. Presently preferred moieties include those wherein A is 1,2,3-triazin-4-yl, 1,2,4-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,3,5-triazin-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl.
In accordance with still another embodiment of the invention, A is a 5-, 6-, or 7-membered ring containing, as ring members, four nitrogen atoms. Moieties contemplated for use in the practice of the invention include those wherein A is tetrazin-2-yl, tetrazin-3-yl, tetrazin-5-yl, tetrazolyl, tetrazepinyl, and the like. Presently preferred moieties include those wherein A is tetrazolyl.
In accordance with yet another embodiment of the invention, A is a 5-, 6-, or 7-membered ring containing, as ring members, one sulfur atom and two nitrogen atoms. Moieties contemplated by this embodiment of the invention include those wherein A is 1,2,6-thiadiazin-3-yl, 1,2,5-thiadiazin-3-yl, 1,2,4-thiadiazin-3-yl, 1,2,5-thiadiazin-4-yl, 1,2,3-thiadiazin-4-yl, 1,3,4-thiadiazin-5-yl, 1,3,4-thiadiazin-2-yl, 1,2,4-thiadiazin-5-yl, 1,3,5-thiadiazin-4-yl, 1,3,5-thiadiazin-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, thiadiazepinyl, and the like. Presently preferred moieties include those wherein A is 1,2,4-thiadiazol-3-yl, 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl.
In accordance with yet another embodiment of the invention, A is a 5-, 6-, or 7-membered ring containing, as ring members, one oxygen atom and two nitrogen atoms. Moieties contemplated by this embodiment of the invention include those wherein A is 1,2,6-oxadiazin-3-yl, 1,2,5-oxadiazin-3-yl, 1,2,4-oxadiazin-3-yl, 1,2,5-oxadiazin-4-yl, 1,2,3-oxadiazin-4-yl, 1,3,4-oxadiazin-5-yl, 1,3,4-oxadiazin-2-yl, 1,2,4-oxadiazin-5-yl, 1,3,5-oxadiazin-4-yl, 1,3,5-oxadiazin-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, oxadiazepinyl, and the like. Presently preferred moieties include those wherein A is 1,2,4-oxadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,3,4-oxadiazol-2-yl, 1,2,5-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl.
In accordance with still another embodiment of the invention, A is a 5-, 6-, or 7-membered ring containing as ring members, one up to six nitrogen atoms, and/or one up to six carbon atoms, and/or zero up to five sulfur atoms, and/or zero up to five oxygen atoms.
Further, in accordance with the present invention, L is a linking moiety which links moieties A and B. L is selected from substituted or unsubstituted alkenylene moieties, alkynylene moieties or azo moieties. Presently preferred compounds of the invention are those wherein L is alkenylene or alkynylene moieties containing two carbon atoms, with alkynylene most preferred.
Further, in accordance with the present invention, B is a moiety linked through bridging moiety L to moiety A. Radicals contemplated for use in the invention are those wherein B is substituted or unsubstituted hydrocarbyl, substituted or unsubstituted cyclohydrocarbyl, substituted or unsubstituted heterocycle, optionally containing one or more double bonds, substituted or unsubstituted aryl, and the like.
Presently preferred compounds of the invention are those wherein B is a substituted or unsubstituted hydrocarbyl selected from substituted or unsubstituted alkyl moieties, alkenyl moieties, dialkenyl moieties, trialkenyl moieties, alkynyl moieties, alkadiynyl moieties, alkatriynyl moieties, alkenynyl moieties, alkadienynyl moieties, alkenediynyl moieties, and the like.
Further preferred compounds of the invention are those wherein B is a substituted or unsubstituted cyclohydrocarbyl selected from substituted or unsubstituted cycloalkyl moieties, cycloalkenyl moieties, cycloalkadienyl moieties, cycloalkatrienyl moieties, cycloalkynyl moieties, cycloalkadiynyl moieties, bicyclic hydrocarbon moieties wherein two rings have two atoms in common, and the like. Especially preferred compounds are those wherein B is cycloalkyl and cycloalkenyl having in the range of 4 up to about 8 carbon atoms.
Still further preferred compounds of the invention are those wherein B is a substituted or unsubstituted heterocycle, optionally containing one or more double bonds. Exemplary compounds include pyridyl, thiazolyl, furyl, dihydropyranyl, dihydrothiopyranyl, piperidinyl, and the like. Also preferred are compounds wherein B is substituted or unsubstituted aryl. Especially preferred compounds are those wherein substituents are methyl, trifluoromethyl and fluoro and wherein B is 3,5-di-trifluoromethyl phenyl.
Those of skill in the art recognize that invention compounds may contain one or more chiral centers, and thus can exist as racemic mixtures. For many applications, it is preferred to carry out stereoselective syntheses and/or to subject the reaction product to appropriate purification steps so as to produce substantially optically pure materials. Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions. Those of skill in the art will further recognize that invention compounds may exist in polymorphic forms wherein a compound is capable of crystallizing in different forms. Suitable methods for identifying and separating polymorphisms are known in the art.
As used herein, with reference to compounds not embraced by the scope of the claims, esterified carboxy is, for example, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl substituted in the phenyl moiety by one or more substituents selected from lower alkyl, lower alkoxy, halo and halo-lower alkyl. Esterified carboxy-lower-alkoxy is, for example, lower alkoxycarbonyl-lower alkoxy. Amidated carboxy is, for example, unsubstituted or aliphatically substituted carbamoyl such as carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted N-phenyl- or N-lower-alkyl-N-phenyl-carbamoyl.
As used herein, with reference to compounds not embraced by the scope of the claims, acyl is, for example, lower alkanoyl, lower alkenoyl or unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or trifluoromethyl-substituted benzoyl. Acyl amino is, for example, lower alkanoylamino, and N-acyl-N-lower alkylamino is, for example, N-lower alkanoyl-N-lower-alkylamino or unsubstituted or lower alkyl-, lower alkoxy-halo- and/or trifluoromethyl-substituted benzoylamino.
As referred to in reference to compounds not embraced by the scope of the claims xe2x80x9clowerxe2x80x9d groups are understood to comprise up to and including seven carbon atoms. N-lower-alkyl-N-phenylcarbamoyl is, for example, Nxe2x80x94C1-C4alkyl-N-phenylcarbamoyl, such as N-methyl, N-ethyl, N-propyl, N-isopropyl or N-butyl-N-phenylcarbamoyl.
As used herein, with reference to compounds not embraced by the scope of the claims, amino-lower alkyl is, for example, amino-C1-C4alkyl, preferably of the formula xe2x80x94(CH2)nxe2x80x94NH2 in which n is 2 or 3, such as aminomethyl, 2-aminoethyl, 3-aminopropyl or 4-aminobutyl. Hydroxy-lower alkyl is, for example, hydroxy-C1-C4alkyl, such as hydroxymethyl, 2-hydroxy ethyl, 3-hydroxypropyl, 2-hydroxyisopropyl or 4-hydroxybutyl. Halo-lower alkyl is, for example, polyhalo-C1-C4alkyl, such as trifluoromethyl.
As used herein, with reference to compounds not embraced by the scope of the claims, lower alkoxy is, for example, C1-C7alkoxy, preferably C1-C4alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but may also represent isobutyloxy, sec.butyloxy, tert.-butyloxy or a C5-C7alkoxy group, such as a pentyloxy, hexyloxy or heptyloxy group.amino-lower alkoxy is, for example, amino-C2-C4alkoxy preferably of the formula xe2x80x94Oxe2x80x94(CH2)nxe2x80x94NRaRb in which n is 2 or 3, such as 2-aminoethoxy, 3-aminopropyloxy or 4-aminobutyloxy. Carboxy-lower-alkoxy is, for example, carboxy-C1-C4alkoxy, such as carboxymethoxy, 2-carboxyethoxy, 3-carboxypropyloxy or 4-carboxybutyloxy. Lower alkanoyloxy is, for example, C1-C7alkanoyloxy, such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy. Halo-lower alkoxy is, for example, halo- or polyhalo-C1-C7alkoxy, preferably halo- or polyhalo-C1-C4alkoxy, such as halo- or polyhaloethoxy, halo- or polyhalopropyloxy or butyl-oxy, wherein xe2x80x9cpolyxe2x80x9d refers, for example, to tri- or pentahalo, and xe2x80x9chaloxe2x80x9d denotes, for example, fluoro or chloro.
As used herein, with reference to compounds not embraced by the scope of the claims, lower alkylamino-lower alkoxy is, for example, C1-C4alkylamino-C2-C4alkoxy, preferably of the formula xe2x80x94Oxe2x80x94(CH2)nxe2x80x94NRaRb in which n is 2 or 3 and Ra and Rb, independently of each other, denote lower alkyl groups as defined hereinbefore, such as methyl, ethyl, propyl or butyl. Lower alkylamino-lower alkyl is, for example, C1-C4alkylamino-C1-C4alkyl, preferably of the formula xe2x80x94(CH2)nxe2x80x94NRaRb in which n is 2 or 3 and Ra and Rb, independently of each other, denote lower alkyl groups as defined hereinbefore, such as methyl, ethyl, propyl or butyl. Di-lower alkylamino-lower alkyl is, for example, Di-C1-C4alkylamino-C1-C4alkyl, preferably of the formula xe2x80x94(CH2)nxe2x80x94NRaRb in which n is 2 or 3 and Ra and Rb, independently of each other, denote lower alkyl groups such as methyl, ethyl, propyl or butyl. Di-lower alkylamino-lower alkoxy is, for example, Di-C1-C4alkylamino-C2-C4alkoxy, preferably of the formula xe2x80x94Oxe2x80x94(CH2)nxe2x80x94NRaRb in which n is 2 or 3 and Ra and Rb, independently of each other, denote lower alkyl groups such as methyl, ethyl, propyl or butyl.
As used herein, with reference to compounds not embraced by the scope of the claims, optionally hydroxy-substituted lower alkyleneamino-lower alkyl is, for example, unsubstituted or hydroxy-substituted 5- to 7-membered alkyleneamino-C1-C4alkyl, preferably of the formula xe2x80x94(CH2)nxe2x80x94Rc in which n is 2 or 3 and Rc pyrrolidino, hydroxypyrrolidino, piperidino, hydroxypiperidino, homopiperidino or hydroxyhomopiperidino. Furthermore, optionally hydroxy-substituted lower alkyleneamino-lower alkoxy is, for example, unsubstituted or hydroxy-substituted 5- to 7-membered alkyleneamino-C1-C4alkoxy, preferably of the formula xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Rc in which n is 2 or 3 and Rc pyrrolidino, hydroxypyrrolidino, piperidino, hydroxypiperidino, homopiperidino or hydroxyhomopiperidino.
In accordance with another embodiment of the present invention, there are provided pharmaceutical compositions comprising heterocyclic compounds as described above, in combination with pharmaceutically acceptable carriers. Optionally, invention compounds can be converted into non-toxic acid addition salts, depending on the substituents thereon, Thus, the above-described compounds (optionally in combination with pharmaceutically acceptable carriers) can be used in the manufacture of medicaments useful for the treatment of a variety of indications.
Pharmaceutically acceptable carriers contemplated for use in the practice of the present invention include carriers suitable for intravenous, subcutaneous, transcutaneous, intramuscular, intracutaneous, intrathecal, inhalation, intracranial, epidural, vaginal, oral, sublingual, rectal, and the like administration. Administration in the form of creams, lotions, tablets, dispersible powders, granules, syrups, elixirs, sterile aqueous or non-aqueous solutions, suspensions or emulsions, patches, and the like, is contemplated.
For the preparation of oral liquids, suitable carriers include emulsions, solutions, suspensions, syrups, and the like, optionally containing additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents, and the like.
For the preparation of fluids for parenteral administration, suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.
Invention compounds can optionally be converted into non-toxic acid addition salts. Such salts are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid. Representative salts include hydrochloride, hydrobromide, sulfate, bisulfate, methanesulfonate, acetate, oxalate, adipate, alginate, aspartate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate (tosylate), citrate, malate, maleate, fumarate, succinate, tartrate, napsylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, undecanoate, 2-hydroxyethanesulfonate, ethanesulfonate, and the like. Salts can also be formed with inorganic acids such as sulfate, bisulfate, hemisulfate, hydrochloride, chlorate, perchlorate, hydrobromide, hydroiodide, and the like. Examples of a base salt include ammonium salts; alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, and the like; and salts with amino acids such as arginine, lysine, and the like. Such salts can readily be prepared employing methods well known in the art.
In accordance with another embodiment of the present invention, there are provided methods for the preparation of heterocyclic compounds as described above. For example, many of the heterocyclic compounds described above can be prepared using synthetic chemistry techniques well known in the art (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984) from a precursor of the substituted heterocycle of Formula 1 as outlined in Scheme 1. 
Thus in Scheme 1, a substituted heterocycle precursor (prepared using synthetic chemistry techniques well known in the art) is reacted with an alkyne derivative. In Scheme 1, (R)q, W, X, Y, Z and B are as defined above and D and E are functional groups which are capable of undergoing a transition metal-catalyzed cross-coupling reaction. For example, D is a group such as hydrogen, halogen, acyloxy, fluorosulfonate, trifluoromethanesulfonate, alkyl- or arylsulfonate, alkyl- or arylsulfinate, alkyl- or arylsulfide, phosphate, phosphinate, and the like, and E is hydrogen or a metallic or metalloid species such as Li, Mgx (X is halogen), SnR3, B(OR)2, SiR3, GeR3, and the like. The coupling may be promoted by a homogeneous catalyst such as PdCl2(PPh3)2, or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g., tetrahydrofuran (THF), dimethoxyethane (DME), acetonitrile, dimethylformamide (DMF), etc.). Typically, a co-catalyst such as copper (I) iodide and a base (e.g., NEt3, K2CO3 etc.) will also be present in the reaction mixture. The coupling reaction typically proceeds by allowing the reaction temperature to warm slowly from about 0xc2x0 C. up to ambient temperature over a period of several hours. The reaction mixture is then maintained at ambient temperature, or heated to a temperature anywhere between 30xc2x0 C. and 150xc2x0 C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to 48 hours, with about 12 hours typically being sufficient. The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation, and the like.
Another embodiment of the present invention is illustrated in Scheme 2. A substituted heterocycle precursor is reacted with an alkene derivative in a manner similar to the procedure described for Scheme 1. 
The alkene derivative product from Scheme 2 may be converted to an alkyne derivative using the approach outlined in Scheme 3. 
Thus, the alkene derivative may be contacted with a halogenating agent such as chlorine, bromine, iodine, NCS (N-chlorosuccinimide), NBS (N-bromosuccinimide), NIS (N-iodosuccinimide), iodine monochloride, etc. in a suitable solvent (CCl4, CHCl3, CH2Cl2, acetic acid, and the like). The resulting halogenated derivative (G=halogen) is then treated with a suitable base such as NaOH, KOH, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (diazabicyclononene), DABCO (1,4-diazabicyclo[2.2.2]octane), and the like, which promotes a double elimination reaction to afford the alkyne. The reaction is carried out in a suitable solvent such as ethanol, acetonitrile, toluene, etc. at an appropriate temperature, usually between about 0xc2x0 C. and 150xc2x0 C.
In another embodiment of the present invention, a substituted heterocyclic derivative is reacted with an aldehyde or ketone to provide a substituted alkene. (See Scheme 4.) 
Thus, in Scheme 4, J is hydrogen, PR3, P(O)(OR)2, SO2R, SiR3, and the like, K is hydrogen, alkyl or aryl (as defined previously) and R is hydrogen, acetyl, and the like. Suitable catalysts for this reaction include bases such as NaH, n-buytllithium, lithium diisopropylamide, lithium hexamethyl disilazide, H2NR, HR2, NR3 etc., or electropositive reagents such as Ac2O, ZnCl2, and the like. The reaction is carried out in a suitable solvent (THF, acetonitrile, etc.) at an appropriate temperature, usually between about 0xc2x0 C. and 150xc2x0 C. Sometimes an intermediate is isolated and purified or partially purified before continuing through to the alkene product.
In yet another embodiment of the present invention, a substituted heterocyclic aldehyde or ketone is reacted with an activated methylene-containing compound to provide a substituted alkene. (See Scheme 5.) 
Thus, in Scheme 5, J, K, R, the catalyst and reaction conditions are as described for Scheme 4. Again, as in Scheme 4, sometimes an intermediate is isolated and purified or partially purified before continuing through to the alkene product.
The alkene products from the reactions in Scheme 4 and Scheme 5 may be converted to an alkyne derivative using reagents and conditions as described for Scheme 3.
Another method for the preparation of heterocyclic compounds of Formula I is depicted in Scheme 6. 
In scheme 6, Y is O or S and G is halogen or a similar leaving group, and L and B are as defined previously. The reagents are contacted in a suitable solvent such as ethanol, DMF, and the like and stirred until the product forms. Typically reaction temperatures will be in the range of ambient through to about 150xc2x0 C., and reaction times will be from about 1 h to about 48 h, with about 70xc2x0 C. and 4 h being presently preferred. The heterocycle product can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation, and the like. Often, the product will be isolated as the hydrochloride or hydrobromide salt, and this material may be carried onto the next step with or without purification.
Yet another method for the preparation of heterocyclic compounds of Formula I is depicted in Scheme 7. 
In Scheme 7, W may be O or S, G is halogen or a similar leaving group, and L and B are as defined previously. The reaction conditions and purification procedures are as described for Scheme 6.
In another embodiment of the present invention, depicted in Scheme 8, an alkynyl-substituted heterocycle precursor (prepared using synthetic chemistry techniques well known in the art) is reacted with a species B, bearing a reactive functional group D (See Scheme 8.) 
In Scheme 8, (R)q, W, X, Y, Z and B are as defined above and D and E are functional groups which are capable of undergoing a transition metal-catalyzed cross-coupling reaction. For example, D is a group such as hydrogen, halogen, acyloxy, fluorosulfonate, trifluoromethanesulfonate, alkyl- or arylsulfonate, alkyl- or arylsulfinate, alkyl- or arylsulfide, phosphate, phosphinate, and the like, and E is hydrogen or a metallic or metalloid species such as Li, MgX (X is halogen), SnR3, B(OR)2, SiR3, GeR3, and the like. The coupling may be promoted by a homogeneous catalyst such as PdCl2(PPh3)2, or by a heterogeneous catalyst such as Pd on carbon in a suitable solvent (e.g. tetrahydrofuran (THF), dimethoxyethane (DME), acetonitrile, dimethylformamide (DMF), etc.). Typically a co-catalyst such as copper (I) iodide and the like and a base (e.g. NEt3, K2CO3, etc.) will also be present in the reaction mixture. The coupling reaction is typically allowed to proceed by allowing the reaction temperature to warm slowly from about 0xc2x0 C. up to ambient temperature over a period of several hours. The reaction mixture is then maintained at ambient temperature, or heated to a temperature anywhere between about 30xc2x0 C. up to about 150xc2x0 C. The reaction mixture is then maintained at a suitable temperature for a time in the range of about 4 up to about 48 hours, with about 12 hours typically being sufficient. The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation, and the like.
Another embodiment of the present invention is illustrated in Scheme 9. 
An alkenyl-substituted heterocycle precursor is reacted with an alkene derivative in a manner similar to the procedure described for Scheme 8. The product alkene derivative from Scheme 9 may be converted to an alkyne derivative using the approach outlined previously in Scheme 3 above.
In yet another embodiment of the present invention, depicted in Scheme 10, an alkynyl-substituted heterocycle precursor is reacted with a species composed of a carbonyl group bearing substituents Rxe2x80x2 and CHRxe2x80x3Rxe2x80x2xe2x80x3. 
Thus in Scheme 10, Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 may be hydrogen or other substituents as described previously, or may optionally combine to form a ring (this portion of the molecule constitutes B in the final compound). E is hydrogen or a metallic or metalloid species such as Li, MgX, wherein X is halogen, SnR3, B(OR)2, SiR3, GeR3, and the like. Suitable catalysts for this reaction include bases such as NaH, n-butyllithium, lithium diisopropylamide, lithium hexamethylsilazide, H2NR, HNR2, NR3, nBu4NF, ethylmagnesium halide, etc. R in Scheme 10 may be hydrogen, Ac, and the like. Typically the reaction is carried out in a suitable solvent such as diethylether, THF, DME, toluene, and the like, and at an appropriate temperature, usually between xe2x88x92100xc2x0 C. and 25xc2x0 C. The reaction is allowed to proceed for an appropriate length of time, usually from about 15 minutes to about 24 hours. The intermediate bearing the xe2x80x94OR group may be isolated and purified as described above, partially purified or carried on to the next step without purification. Elimination of the xe2x80x94OR group to provide the alkene derivative may be accomplished using a variety of methods well known to those skilled in the art. For example, the intermediate may be contacted with POCl3 in a solvent such as pyridine and stirred at a suitable temperature, typically between about 0xc2x0 C. and about 150xc2x0 C., for an appropriate amount of time, usually between about 1 h and about 48 h. The product from the reaction can be isolated and purified employing standard techniques, such as solvent extraction, chromatography, crystallization, distillation, and the like.
The following examples are intended to illustrate but not to limit the invention in any manner, shape, or form, either explicitly or implicitly. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skill in the art may alternatively be used.